Discovery could lead to more effective treatments for amphetamine abuse and brain disease

Results from a government-funded study at Johns Hopkins provide what is believed to be the first evidence in people that amphetamines have a greater effect on men's brains than women's -- a discovery that could lead to tailored treatments for drug abuse and neurological diseases.

The study, led by Gary S. Wand, M.D., a professor of endocrinology in the Department of Medicine at Johns Hopkins School of Medicine, found that men's brains showed evidence of up to three times the amount of chemical dopamine as women's when exposed to amphetamines.

The study will be published July 1 in The Journal of Biological Psychiatry.

Dopamine is a neurotransmitter or chemical activator that also works like a hormone. In the brain, it can increase heart rate and blood pressure and is critical to the way the brain controls movement. Commonly linked to the brain's so-called pleasure system, dopamine is released in the presence of such high-producing drugs as amphetamines and cocaine, and shortages are associated with Parkinson's disease, memory loss, depression and other mental illnesses.

"These appear to be the first clinical studies whose results may help explain why we see a greater number of men abusing amphetamines than women," Wand stated. According to the Substance Abuse and Mental Health Services Administration (SAMHSA), 6 percent of American males and 3.8 percent of females, 12 and older, illegally used amphetamines in 2004. Wand said the finding may also explain the higher incidence of amphetamine-induced neurotoxicity in males compared to females.

Amphetamines stimulate the central nervous system, with effects lasting anywhere from four to 24 hours. The drug has been linked to heart failure, brain damage, stroke, kidney and lung disorders, liver damage, blood clots, malnutrition, deficient immune systems, hyperthermia and convulsions. The drug has also been linked to acute psychiatric and psychological symptoms that may lead to suicide or murder.

The Hopkins study focused on dopamine release in an area in the center of the brain called the striatal region. Studies have already shown that amphetamine-stimulated dopamine release in the striatum differs in male and female mice. This is the first time, however, that studies in humans have substantiated these findings, Wand said.

The so-called pleasure experience happens when dopamine released by one brain cell is taken up by dopamine receptors in another. To measure the amount of dopamine stimulated by amphetamine, researchers introduced a drug, Raclopride C11, into the bloodstream that not only binds with dopamine receptor sites but also relinquishes these sites if available dopamine is present.

Raclopride C11 is an antipsychotic drug, Raclopride, that carries a radioactive tag, C11, that can be read using a positron emission tomography (PET) scan. The doses of Raclopride C11 administered in this study were well below therapeutic levels.

For the purpose of the Hopkins study, potential test subjects first had to pass an extensive medical screening process to ensure that they were healthy and normal in regard to factors such as overall health and fitness, drug and alcohol use and psychological condition. Once the screening process was completed, 43 individuals, ranging in age from 18 to 29 years, were chosen. Of that group, 28 were men and 15 were women.

In the first PET scan, Raclopride C11 and saline were introduced into the bloodstream by injection. In the absence of amphetamine-stimulated dopamine release, available receptors bound with Raclopride C11. This gave researchers a PET scan level that indicated the total number of available dopamine receptors. Results indicated an equal number of dopamine receptors for both males and females in the study group.

In the second PET scan, amphetamines were injected intravenously with Raclopride C11. Since Raclopride C11 only bound to receptors not already filled by dopamine, PET scan levels gave researchers a clear indication of the amount of dopamine released between neurons. In this session, results showed a higher level of dopamine release for men in the ventral striatum and three out of four of the other striatal areas scanned.

The study also looked at subjective responses to amphetamine in the bloodstream. Participants were asked to verbally rate their experiences, including positive effects (high, rush, good effect, liking and desire for the drug) and negative effects (fidgetiness, anxiety, dizziness, dry mouth and distrust). Subjective responses for males were significantly higher in all but one category, dizziness. In that category, women rated higher.

"The fact that the subjective tests supported the biological ones further supports the hypothesis that men exhibit a higher response to amphetamines than women," Wand said.

Since it is known that the drug reward is related to dopamine release in the ventral striatum, this study strongly suggests that men undergo more reinforcement from amphetamines than women. This in turn could help researchers and clinicians treat people with amphetamine abuse issues.

Wand said this study might also help researchers learn more about the sexual differences related to neuropsychiatric diseases that involve the other areas of the striatum that were tested. These diseases include Parkinson's disease, schizophrenia, Huntington's diseases, obsessive compulsive disorder and Tourette syndrome.